Prodrug Strategies for HCV Nucleoside Lead Development

HCV 核苷先导药物开发的前药策略

• 批准号: 8415492
• 负责人: Katherine L Seley-Radtke
• 金额: $ 20.58万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415492
• 关键词: Adverse effects; Antiviral Agents; Biological Assay; Cell Culture Techniques; Clinical Trials; Combined Modality Therapy; Development; Diphosphates; Disease; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Drug resistance; Exhibits; Genotype; Guanosine; Hand; Hepatitis C virus; Hepatocyte; Industry; Interferons; Knowledge; Laboratories; Lead; Life; Liver; Liver diseases; Masks; Metabolism; Methodology; Methods; Moderate Exercise; Modification; Mono-S; Nucleosides; Nucleotides; Parents; Patients; Plague; Plasma; Polymerase; Prodrugs; Purine Nucleosides; RNA-Directed RNA Polymerase; Radiolabeled; Relative (related person); Replicon; Reporting; Research; Research Personnel; Ribavirin; Risk; Series; Structure; Students; Techniques; Therapeutic; Thiophenes; Time; Toxic effect; Training; Virus Diseases; Work; analog; anti-hepatitis C; cytotoxicity; design; effective therapy; global health; improved; in vivo; inhibitor/antagonist; nucleoside analog; phosphoramidite; radiotracer; small molecule; stem; tripolyphosphate; uptake; viral RNA

DESCRIPTION (provided by applicant): More than 200 million people worldwide are estimated to be chronically infected with HCV and as a result, at risk for developing life-threatening liver diseases. The only treatment currently available is a combination therapy of pegylated interferon and Ribavirin, a nucleoside analogue. Unfortunately this combination has exhibited limited efficacy in less than half of treated patients, as well as being plagued with treatment- limiting side effects and toxicity. In addition, increasing reports of drug resistance to investigational small molecules in clinical trials are emerging, underscoring the need for new and more effective treatments. A number of modified nucleosides have exhibited potent activity as inhibitors of HCV polymerase, however problems with ineffective delivery, toxicity, instability and/or poor pharmacokinetics have rendered many promising analogues unsuitable, thus many researchers are turning to use of a prodrug, or "masking" group, on the 5'-OH of the nucleoside, to overcome these problems. This application focuses on a series of expanded purine nucleoside analogues that we anticipate will exhibit potent activity against the HCV RNA-dependent RNA polymerase (RdRp) NS5B due to a number of strategically designed structural features. The impact of this application is two-fold; one, the medicinal discoveries could ultimately have a global impact, as more effective HCV treatments are desperately needed. In addition, the basic scientific impacts include expanding the breadth of our knowledge of drug delivery methods for specific targeting of the HCV NS5B polymerase, as well as liver cells. In addition, new and improved methodology for nucleoside analogue synthesis will be investigated. As such, the scientific impact of this work goes beyond just global health research, but will also provide valuable training for students, as the synthetic organic and drug delivery methodologies and the information obtained about polymerases will be highly applicable across a broad scope of diseases.

描述(由申请人提供)：据估计，全球有超过2亿人长期感染丙型肝炎病毒，因此有发展成危及生命的肝病的风险。目前唯一可用的治疗方法是聚乙二醇化干扰素和核苷类似物利巴韦林的联合治疗。不幸的是，这种组合在不到一半的接受治疗的患者中表现出有限的疗效，并受到治疗限制副作用和毒性的困扰。此外，在临床试验中出现了越来越多的对研究用小分子的耐药性报告，这突显了对新的、更有效的治疗方法的需要。许多修饰的核苷作为丙型肝炎病毒聚合酶的抑制剂表现出了很强的活性，但由于药物传递效率低、毒性大、不稳定性和/或药代动力学不佳等问题，使得许多有希望的类似物不再适用，因此许多研究人员正转向在核苷的5‘-OH上使用前药或掩蔽基团来克服这些问题。本申请重点介绍了一系列扩展的嘌呤核苷类似物，由于一些战略性设计的结构特征，我们预计这些类似物将显示出强大的抗丙型肝炎病毒RNA依赖RNA聚合酶(RdRp)NS5B的活性。这项应用的影响是双重的；第一，药物发现最终可能产生全球影响，因为迫切需要更有效的丙型肝炎病毒治疗方法。此外，基本的科学影响包括扩大我们对特定靶向丙型肝炎病毒NS5B聚合酶和肝细胞的药物输送方法的知识广度。此外，还将研究核苷类似物合成的新方法和改进方法。因此，这项工作的科学影响不仅限于全球卫生研究，还将为学生提供宝贵的培训，因为合成有机和药物输送方法以及获得的关于聚合酶的信息将高度适用于广泛的疾病范围。